Typically, infection with the human immunodeficiency virus, HIV-1, eventually causes acquired immunodeficiency syndrome (AIDS) and an associated syndrome, AIDS-related complex (ARC). Neutralizing this virus has proved difficult, largely because its structure obstructs immune system access to viral epitopes and its genetic material is highly variable. Accordingly, researchers have been seeking prophylactic and therapeutic methods for preventing or controlling HIV which are not dependent upon antibody-mediated immunity.
The HIV retrovirus replicates in certain immune system cells, specifically the CD4+ subset of T-lymphocytes (pre-Th cells arising in the thymus). In the usual course of a cell-mediated immune response to an intracellular pathogen such as a virus, dendritic cells (antigen-presenting cells) carrying antigen fragments and secreted cytokines activate these CD4+ T-cells. Activated cells, called T-helper or Th cells, in turn secrete their own cytokines and stimulate macrophages. CD4+Th cells also propagate cellular immune response by binding chemotactic cytokines (chemokines, CCs) to their CC surface receptors. It is by this route that HIV-1 infection of these cells is enabled because, in addition to binding chemokines, these CC receptors act together with the CD4+ surface glycoprotein as coreceptors for HIV-1 and mediate entry of the virus into the CD4+Th cell. There, the virus usurps the native genetic material for viral replication while destroying cell functions essential for building immunity; the increasing destruction of these cells appears to be responsible for the eventual collapse of the cell-mediated immune system often seen in terminal AIDS patients.
It has been recognized that denying entry into CD4+ cells to the HIV-1 virus could at least slow the progress of the infection and alleviate, if not cure, the disease and/or its symptoms. The complex mechanism by which the virus crosses the cell membrane has been widely investigated. Broadly, the entry of human immunodeficiency virus into, for example, CD4+ Th1 cells (T-helper type 1 cells, is dependent upon a sequential interaction of the gp120/gp41 subunits of the viral envelope glycoprotein gp160 with the CD4+Th1 cell surface glycoprotein and the cell surface receptor CCR5. On binding of gp120 with its cell surface binding sites, a conformational change in the latent gp41 subunit through an intermediate state to an active state is initiated, inducing fusion of the viral and cellular membranes and transport of the virus into the cell (Nature 387:426-30, 1997).
Accordingly, numerous binding experiments have been conducted in an effort to find antiviral ligands that will effectively compete with the HIV-1 for CD4+ gp and/or CCR5 binding sites, or that will preferentially block gp120 and/or gp41 binding domains. In one example, a reported structure (X-ray crystallography) comprising an HIV-1 gp120 core complexed with a two-domain fragment of human CD4 and an antigen-binding fragment of a neutralizing antibody that blocks chemokine-receptor binding, is said to reveal a CD4-gp120 interface, a conserved binding site for the chemokine receptor, evidence for a conformational change on CD4 binding, the nature of a CD4-induced antibody epitope, and specific mechanisms for viral immune evasion, “which should guide efforts to intervene” (Nature 393 (6686):632-1, 1998). Also, it has been shown that inhibition of the change in structure of gp41 from its intermediate to active state with peptides used as competitors for critical cell receptors may reduce viral load, and that while gp120 masks epitopes on the gp41 subunit in its latent state, gp41 may be vulnerable to neutralizing antibodies in its transient or intermediate state (Molecular Membrane Biology 16:3-9, 1999). In another study, disclosed in U.S. Patent Application Publication US 2004/0018639 A1, filed Jun. 3, 2003, published Jan. 29, 2004, by Zhabilov et al. the content of which is incorporated herein in its entirety by reference, a protein designated “Thymus Factor” (“TF”) is stated to have the ability to bind to a fragment of HIV-1 gp41 in gel electrophoresis, and that this binding property can be used to assay TF activity or in the treatment of HIV.